Exceptional synergistic response of PARP inhibitor and immune checkpoint inhibitor in esophageal adenocarcinoma with a germline BRCA2 mutation: a case report.

Immune checkpoint inhibitors (ICIs) and poly (ADP-ribose) polymerase (PARP) inhibitors have shown efficacy in various tumors. A significant therapeutic challenge with either ICIs or PARP inhibitors as monotherapy is treatment failure from intrinsic primary resistance or the development of secondarily acquired resistance after a period of responsiveness. The combination of PARP inhibitors and ICIs could mitigate this by potentiating treatment response. We describe an 83-year-old male patient who initially presented with abdominal pain, and weight loss along with alternating constipation and diarrhea. Imaging and biopsy revealed metastatic esophageal adenocarcinoma. Genomic testing revealed germline BRCA2 mutation. The patient initially underwent a few cycles of chemoimmunotherapy. However, due to intolerance to chemotherapy, the patient's case was discussed at a multidisciplinary molecular tumor board. He was switched to PARP inhibitor olaparib and ICI nivolumab. This combination led to a durable complete response. A combination of poly-ADP ribose polymerase inhibitor (PARPi) plus ICI may work in synergy through various mechanisms including enhanced neoantigen expression, release of immune-activating cytokines, and increased programmed death-ligand 1 expression. This may culminate in accentuated efficacy outcomes with a manageable safety profile. This exceptional response with ICI and PARPi in our case is consistent with the synergistic value of this combination, and prospective studies are warranted to definitively characterize clinical utility.

Non-Invasive Predictive Biomarkers for Immune-Related Adverse Events Due to Immune Checkpoint Inhibitors.

Immune-related adverse events (irAEs) are the most common complication of immune checkpoint inhibitor (ICI) therapy. With the widespread use of ICIs in patients with solid tumors, up to 40% of the patients develop irAEs within five months of treatment, and 11% develop severe irAEs requiring interventions. A predictive test for irAEs would be a crucial tool for monitoring for complications during and after ICI therapy. We performed an extensive review of potential predictive biomarkers for irAEs in patients who received ICI therapy. Currently, only thyroid-stimulating hormone is utilized in common clinical practice. This is due to the unavailability of commercial tests and unclear predictive values from various studies. Given the lack of single strong predictive biomarkers, some novel approaches using composite scores using genomic, transcriptomics, cytokine levels, or clinical parameters appear appealing. Still, these have yet to be validated and incorporated into clinical practice. Further research conducted to validate the models before implementing them into real-world settings will be of the utmost importance for irAE prediction.

Response to osimertinib in a colorectal cancer patient with an EGFR T790M mutation: A case report.

BACKGROUND: Although common in lung cancer, somatic epidermal growth factor receptor (EGFR) mutations are rarely found in colorectal cancer, occurring in approximately 3% of cases. Treatment with anti-EGFR antibodies is commonplace, but EGFR tyrosine kinase inhibitors are not standard treatments in colorectal cancer. Here we report a case of sustained response to osimertinib in a colorectal cancer patient with an EGFR T790M mutation on cell-free DNA analysis. CASE SUMMARY: A 72-year old woman with a past medical history of post-polio syndrome confined to a wheelchair, scoliosis and hypothyroidism presented with metastatic sigmoid colon adenocarcinoma with hepatic metastases. Next generation sequencing revealed a RAS/RAF wild-type, microsatellite stable, PD-L1 negative malignancy. Mutations in TP3 and APC were also identified, as well as EGFR amplification. Cell-free DNA analysis revealed an EGFR T790M mutation. She was unable to tolerate first-line treatment with panitumumab, 5-fluorouracil and leucovorin, progressed on second-line treatment with trifluridine/tipiracil plus bevacizumab, and was unable to tolerate third-line treatment with regorafenib. She was started on fourth-line treatment with off-label osimertinib, with clinical response - decrease in size of hepatic metastases and a pericardial effusion. She remained on treatment with osimertinib for seven months. CONCLUSION: This case shows the benefit of multi-gene sequencing assays to identify potential therapeutic options in patients with refractory disease.

Utility of RNA Expression to Determine the Tissue of Origin of Malignancies with an Inconclusive Histopathology.

We present 2 cases of cancer of unknown origin in which RNA-based cancer classification testing provided vital insight and directed treatment management. The tissue of origin could not be determined in both of these patients utilizing morphology and immunohistochemical analysis of the tissue samples. Next-generation sequencing and tumor-of-origin testing using an RNA-based molecular cancer classifier were performed to elucidate the possible tissue of origin. A 61-year-old male with a history of localized basal cell carcinoma presented with a 4.4-cm axillary lymph node in addition to upper extremity edema and supraclavicular lymphadenopathy. RNA-based tumor origin testing revealed skin basal or squamous cell carcinoma as the likely tissue of origin, with a probability of 97%. He received vismodegib, a hedgehog inhibitor, after progression on cemiplimab and experienced a partial response by RECIST criteria, which is currently ongoing for over a year. A 74-year-old female patient with a remote history of ovarian cancer for which she underwent resection and adjuvant chemotherapy presented 15 years later with abdominal pain. The diagnostic workup revealed a 2-cm pancreatic mass and enlarged peritoneal lymph nodes. RNA sequencing revealed a 99% likelihood of the tissue of origin being serous ovarian carcinoma. Subsequently, she underwent surgery and adjuvant chemotherapy and is currently in remission with letrozole maintenance. Genomic data already plays a crucial role in therapeutic decision-making for individuals with cancer. These cases highlight the complementary role of genomic data in the diagnostic workup of cancer, leading to favorable patient outcomes.

Transmission of Lung Adenocarcinoma From a Single Donor in 2 Transplant Recipients: A Case Report With Literature Review.

Malignancies transmitted to recipients during solid organ transplants carry significant morbidity and mortality. We present 2 cases of adenocarcinoma of donor lung origin transmitted via liver and kidney transplant from a single donor. Both recipients developed metastatic adenocarcinoma of lung origin with p.L858R mutation in the epidermal growth factor receptor gene and a microsatellite signature of donor origin. Osimertinib was trialed in the liver recipient; however, it was discontinued because of hepatotoxicity and disease progression. Standard donor screening protocols limit malignancy transmission but do not include multicancer detection assays. As these technologies evolve, they may be implemented in donor screening.

Immunotherapy and Immunotherapy Combinations in Metastatic Castration-Resistant Prostate Cancer.

Although most prostate cancers are localized, and the majority are curable, recurrences occur in approximately 35% of men. Among patients with prostate-specific antigen (PSA) recurrence and PSA doubling time (PSADT) less than 15 months after radical prostatectomy, prostate cancer accounted for approximately 90% of the deaths by 15 years after recurrence. An immunosuppressive tumor microenvironment (TME) and impaired cellular immunity are likely largely responsible for the limited utility of checkpoint inhibitors (CPIs) in advanced prostate cancer compared with other tumor types. Thus, for immunologically "cold" malignancies such as prostate cancer, clinical trial development has pivoted towards novel approaches to enhance immune responses. Numerous clinical trials are currently evaluating combination immunomodulatory strategies incorporating vaccine-based therapies, checkpoint inhibitors, and chimeric antigen receptor (CAR) T cells. Other trials evaluate the efficacy and safety of these immunomodulatory agents' combinations with standard approaches such as androgen deprivation therapy (ADT), taxane-based chemotherapy, radiotherapy, and targeted therapies such as tyrosine kinase inhibitors (TKI) and poly ADP ribose polymerase (PARP) inhibitors. Here, we will review promising immunotherapies in development and ongoing trials for metastatic castration-resistant prostate cancer (mCRPC). These novel trials will build on past experiences and promise to usher a new era to treat patients with mCRPC.

Proteasome inhibitor associated thrombotic microangiopathy.

A variety of medications have been implicated in the causation of thrombotic microangiopathy (TMA). Recently, a few case reports have emerged of TMA attributed to the proteasome inhibitors (PI) bortezomib and carfilzomib in patients with multiple myeloma. The aim of this case series was to better characterize the role of PI in the etiology of drug-induced TMA. We describe eleven patients from six medical centers from around the world who developed TMA while being treated with PI. The median time between medication initiation and diagnosis of TMA was 21 days (range 5 days to 17 months). Median laboratory values at diagnosis included hemoglobin-7.5 g dL(-1) , platelet count-20 × 10(9) /L, LDH-698 U L(-1) , creatinine-3.12 mg dL(-1) . No patient had any other cause of TMA, including ADAMTS13 inhibition, other malignancy or use of any other medication previously associated with TMA. Nine patients had resolution of TMA without evidence of hemolysis after withdrawal of PI. Two patients had stabilization of laboratory values but persistent evidence of hemolysis despite medication withdrawal. One patient had recurrence of TMA with rechallenge of PI. There is a strong level of evidence that PI can cause DITMA. In evaluating patients with suspected TMA, PI use should be recognized as a potential etiology, and these medications should be discontinued promptly if thought to be the cause of TMA. Am. J. Hematol. 91:E348-E352, 2016. © 2016 Wiley Periodicals, Inc.